# Cytoplasmic cyclin E is an early event for progression to invasive breast cancer

> **NIH NIH R01** · UNIVERSITY OF TX MD ANDERSON CAN CTR · 2020 · $1

## Abstract

Project Summary
Cyclin E, a key regulatory protein controlling the G1 to S phase transition in mammalian cells, is post-
translationally modified by neutrophil elastase mediated proteolytic cleavage to generate the low molecular
weight isoforms of cyclin E (LMW-E) that are detected in many cancer types. Our laboratory has elucidated
several distinct oncological attributes of LMW-E versus full length cyclin E (EL) in breast cancer, using in vitro
and in vivo model systems. In this application, using a robust inducible murine transgenic model of LMW-E
mediated tumorigenesis, we have mapped some of the early events in the pre-neoplastic mammary gland that
gives rise to aggressive tumors with high metastatic potential. These LMW-E oncogenic events permit the
induction of sustained tumorigenesis even in the absence of LMW-E expression. These events include
induction of DNA damage, upregulation of several genes involved in unregulated DNA replication and G2/M
transition, and specific mutations in genes, such as ALK, that is readily targetable. These preliminary results
have led to the following three testable hypotheses: (1) expression of LMW-E early in the pre-invasive breast
cancer (i.e. ductal carcinoma in situ) results in induction of genomic alteration leading to an invasive
carcinoma, (2) LMW-E in a cyclin E knockout model will result in a more aggressive phenotype than
overexpression of EL, resulting in increased genomic instability, centrosome amplification and transformability
in hMECs, (3) Inhibition of ALK, a secondary oncogenic event to LMW-E induction, early in the neoplastic
process can inhibit tumorigenesis and also be used as a target for the treatment of triple negative breast
cancers (TNBC) expressing LMW-E. The following aims are designed to test each aspect of these 3
hypotheses: Aim 1:Examine the role of cytoplasmic cyclin E in differentiating indolent versus high-risk ductal
carcinoma in situ (DCIS). Aim 2: Investigate the mechanism of LMW-E mediated DNA damage response and
centrosome amplification in the absence of endogenous cyclin E in somatic hMEC models. Aim 3: Investigate
the role of ALK as a mediator of LMW-E mediated mammary tumorigenesis and as a therapeutic target in
TNBC. These studies have the potential to identify LMW-E-induced early oncogenic events and provide the
rationale to use LMW-E as a biomarker to identify the DCIS cases which are at high risk for developing
invasive cancer. Our studies will show if ALK can be a viable target for the LMW-E overexpressing TNBC
patients. Since there are already several ALK inhibitors, which have undergone Phase I-III clinical trials in
malignancies other than breast, the translational of these pre-clinical studies to TNBC patients could occur
readily.

## Key facts

- **NIH application ID:** 9859207
- **Project number:** 5R01CA223772-03
- **Recipient organization:** UNIVERSITY OF TX MD ANDERSON CAN CTR
- **Principal Investigator:** KHANDAN KEYOMARSI
- **Activity code:** R01 (R01, R21, SBIR, etc.)
- **Funding institute:** NIH
- **Fiscal year:** 2020
- **Award amount:** $1
- **Award type:** 5
- **Project period:** 2018-02-01 → 2024-01-31

## Primary source

NIH RePORTER: https://reporter.nih.gov/project-details/9859207

## Citation

> US National Institutes of Health, RePORTER application 9859207, Cytoplasmic cyclin E is an early event for progression to invasive breast cancer (5R01CA223772-03). Retrieved via AI Analytics 2026-05-23 from https://api.ai-analytics.org/grant/nih/9859207. Licensed CC0.

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